Tunable DNA-nanostructure to induce NK-mediated killing of tumor cells Summary Antibodies are important recognition molecules that have been widely used in cancer diagnosis and cancer therapy. Aptamers, which are nucleic acid-based recognition molecules, have also been exploited for biomedical applications, partly attributed to their robust nature in synthesis and selection for specific binding activity, similar to antibodies. We propose to develop multivalent aptamers linked onto tunable DNA-nanostructure that bind specifically to both the effector cell and tumor cells, thus are able to engage their interactions, which will trigger the activation of immune effector cells to facilitate destruction of tumor cells. We will focus on constructing multi-valent and multi-specific aptamers linked on DNA-nanoscaffolds to direct natural killer (NK) cells to attack tumor cells. This will be achieved by combining rational design of programmable DNA-nanoscaffolds with systemic selection of aptamer libraries. In addition, the scalable feature of the DNA-nanostructure platform makes it possible to incorporate additional immune modulating ligands to coordinate and synergize various lines of host immunity against cancer cells, including both humoral and cellular immune responses. Thus, these aptamer DNA-nanostructures can potentially function as "magic bullets" for cancer therapy, as well as therapeutics for other diseases. PUBLIC HEALTH RELEVANCE: We propose to develop a novel tumor-killing DNA-nanostructure, in which multimeric cell- recognition aptamers will be assembled onto tunable and programmable DNA-nanoscaffolds to engage immune cells to attack tumor cells.